(Adapted from Investigator's abstract): CD1 is a family of MHC class I- like proteins which appear to function as specialized antigen presenting molecules. Although humans have five CD1 genes, mice encode only a recently duplicated CD1 gene which is homologous to human CD1d. CD1d is the ligand or antigen presenting molecule recognized by a conserved population of CD4plus or CD4minusCD8minus (double negative), NKR-P1plus T-cells that use an invariant TCRa chain and a restricted repertoire of TCR Vb genes (invariant NKR-P1 T-cells). The striking conservation of CD1d and CD1d reactive invariant NKR-P1 T-cells in mice and humans indicates a significant function which is almost certainly to regulate certain aspects of the immune system. The initial observation that invariant NKR-P1 T-cells were a major early source of IL-4 in vivo suggested a direct role in regulating Th1 versus Th2 immune responses, but such a role has not yet been confirmed. Recent studies in humans and mice of autoimmune diseases including systemic lupus erythematosus (SLE), insulin dependent diabetes mellitus (IDDM), and systemic sclerosis have demonstrated quantitative and/or qualitative defects in invariant NKR-P1 T-cells, suggesting an alternative function for these cells in regulating autoimmunity. In particular, studies in IDDM have shown reduced numbers of invariant NKR-P1 T-cells and a striking defect in IL-4 production. The overall objectives of this application are to test the general hypothesis that CD1d and invariant NKR-P1 T-cells play roles in controlling autoimmunity and to test the specific hypothesis that this control is mediated through direct interactions between these CD1d reactive T-cells and potentially autoreactive CD1dplus lymphocytes. Aim 1 will test the hypothesis that defects in these cells occur frequently in human autoimmune disease. Aim 2 will test the hypothesis that invariant NKR-P1 T-cells target autoreactive CD1dplus lymphocytes and identify the factors which contribute to this interaction. Finally, Aim 3 will use CD1d knockout mice as a model system to test the hypothesis that CD1d and invariant NKR-P1 T-cells regulate autoimmunity and the hypothesis that the targets for these cells are mature lymphocytes.